Abstract: Anemia is a common complication among patients with chronic kidney disease (CKD) and traditionally erythropoietin (EPO) deficiency has been considered the major cause. It is clear however that several mechanisms including inflammation contribute to the pathogenesis and an in-depth understanding of all causal mechanisms is key to developing a comprehensive therapeutic strategy. Recent advances point to the emerging association of mitochondrial injury with uremia, oxidative stress and inflammation. Mitochondria have key roles in the marrow response to EPO and heme synthesis. We propose that mitochondrial injury in marrow progenitor cells is important in the pathogenesis of the anemia of CKD. We will use peripheral blood lymphocytes which are descended from common progenitors as a reporter cell to test this hypothesis in patients with CKD and end stage kidney disease. Mitochondrial DNA mutations will be identified and mitochondrial content measured in peripheral blood lymphocytes and their relationship to development of anemia and response to EPO examined in patients with advanced CKD. In this revised application, we will also examine the effect of increasing mitochondrial content by exercise and pioglitazone on anemia in study subjects. Finally we will examine CD34+ cells harvested from the peripheral blood of patients on dialysis and healthy individuals, for markers of mitochondrial injury and then study their proliferation and erythroid differentiation using an in vitro differentiation assay. Quantitative parameters of erythroid proliferation and differentiation will be compared between healthy individuals and patients on dialysis. The results of this proposal will provide new insight into the pathogenesis of anemia in patients with CKD with scope for novel therapeutic strategies.